Pathogenesis of Hyperthyroidism

• The natural history of a non-toxic multi nodular goiter (MNG):
  • Involves variable growth of individual nodules:
    • This may progress to hemorrhage and degeneration:
      • Followed by:
        • Healing and fibrosis
    • Calcification:
      • May be found in areas of previous hemorrhage
  • Some nodules may develop autonomous function:
    • Autonomous hyperactivity:
      • Is conferred by somatic mutations of thyrotropin or thyroid-stimulating hormone receptor (TSHR):
        • In 20% to 80% of toxic adenomas and some nodules of MNGs
      • Autonomously functioning nodules:
        • May become toxic in 10% of patients
      • Hyperthyroidism predominantly occurs:
        • When single autonomous nodules are larger than 2.5 cm in diameter:
          • However, in geographic areas with iodine deficiency, smaller autonomous nodules:
            • May produce systemic, clinical manifestations of hyperthyroidism
  • The development of hyperthyroidism in MNG takes many years:
    • The process evolves from:
      • A small gland with one small nodule or more to nodules increasing progressively in number, size, and function
    • Initially, most patients are euthyroid:
      • But with enlarging goiters, autonomy develops:
        • Illustrated by low or suppressed serum thyroid-stimulating hormone (TSH) with normal serum levels of thyroid hormones
• Graves’ disease:
  • Is a syndrome that consists of:
    • Hyperthyroidism
    • Goiter
    • Ophthalmopathy (orbitopathy)
    • Occasionally a dermopathy referred to as:
      • Pretibial or localized myxedema
  • Hyperthyroidism:
    • Is the most common feature of Graves’ disease:
      • Affecting nearly all patients
    • It is caused by autoantibodies to the TSHR (TSHR-Ab):
      • That activate the receptor:
        • Thereby stimulating thyroid hormone synthesis and secretion:
          • As well as thyroid growth:
            • Causing a diffuse goiter
  • The histology of the thyroid gland in patients with Graves’ hyperthyroidism:
    • Is characterized by:
      • Follicular hyperplasia
      • A patchy (multifocal) lymphocytic infiltration
      • Rare lymphoid germinal centers:
        • The majority of intra-thyroidal lymphocytes are:
          • T cells:
            • Germinal centers (B cells) are much less common than in chronic autoimmune thyroiditis (Hashimoto’s disease)
      • Thyroid epithelial cell size:
        • Correlates with the intensity of the lymphocytic infiltrate:
          • Suggesting thyroid cell stimulation by local B cells secreting TSHR-Ab
    • The presence of TSHR-Ab antibodies:
      • Is positively correlated with:
        • Active diseaseand with relapse of the disease
  • There is an underlying genetic predisposition:
    • Because of an increased frequency of haplotypes human leukocyte antigen:
      • HLA-B8 and HLA-DRw3 in white patients
      • HLA-Bw36 in Japanese patients
      • HLA-Bw46 in Chinese patients
    • However, it is not clear what triggers the acute episodes:
      • Some factors that may incite the immune response are:
        • Pregnancy:
          • Particularly the postpartum period
        • Iodine excess:
          • Particularly in geographic areas of iodine deficiency
      • Lithium therapy
      • Viral or bacterial infections
      • Glucocorticoid withdrawal
  • The etiology and pathogenesis of Graves’ ophthalmopathy are not known:
    • It may involve cytotoxic lymphocytes and cytotoxic antibodies:
      • Sensitized to a common antigen found in:
        • Orbital fibroblasts, orbital muscle, and thyroid tissue:
          • Which may cause inflammation:
            • Resulting in proptosis of the globes
    • It has been suggested recently that TSHR-bearing circulating fibroblasts and fibrocytes:
      • May be activated directly by the TSHR-Ab
  • The pathogenesis of dermopathy may also involve this mechanism:
    • Patients with exophthalmos and particularly those with dermopathy:
      • Almost always have high titers of circulating TSHR autoantibodies:
        • Suggesting that these two clinical manifestations represent the most severe form of this disease

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